Cellular and molecular mechanisms governing immune tolerance to protein and gene replacement therapy in hemophilia (TolerEight)

Protein and Gene Therapies (GT) are innovative treatment options for numerous diseases, with several products recently receiving market authorization. The hosts immune response to delivered proteins, vectors, and transgenes, however, remains a major obstacle, with knowledge of the major pathways regulating this response, lacking. To overcome current obstacles in this field, a joint effort by expert scientists from various disciplines is needed. Hemophilia A (HA), a hemorrhagic disorder mainly caused by F8 gene mutations, is being extensively approached by protein and GT and represents an ideal model to address these issues. One of the most challenging complications (>35–40%) is the development of inhibitory alloantibodies against the infused FVIII protein, and the immune response to viral vectors and F8 transgene following GT. The TolerEight project, based on the collaboration of 2 scientific teams with interdisciplinary expertise in gene therapy and immune response in HA, aims to join forces to conduct an ambitious research program that will lead to the identification of the key cellular and molecular mechanisms involved in long term acceptance of advanced therapies for HA. TolerEight will achieve this by taking advantage of state-of-the-art methodologies, innovative tools, and in vivo preclinical models, including new GT vectors targeting F8 to specific tissues or cells, Tg mouse models for HA expressing trace amounts of residual FVIII, and innovative conditional mouse models devoid of selected cells and immune cellular pathways. Our interdisciplinary approach aims at deciphering intra-and intercellular signaling synergies involved in immune tolerance to the successful and durable FVIII therapies. Specifically, Tolereight aims at: i. defining the role of antigen-presenting cells (APCs) and checkpoint pathways in the immune response to FVIII following FVIII protein replacement and GT; ii. dissecting the impact of residual FVIII expression in anti-FVIII immune responses following protein and gene replacement therapy; iii. to translate the experimental findings to HA patients. If successful, even in part, the project will provide a roadmap that will advance both basic and translational knowledge on the major molecular and cellular determinants of immune responses to FVIII protein and gene replacement therapies for HA. This in turn will help in predicting the immune response and favor immune tolerance tailored to FVIII patients. Further, these findings may also offer hope to many other genetic disorders in the development and optimization of future innovative therapeutic strategies, with significant benefits for both patients and national healthcare systems.